Clinicopathologic features and molecular characterization of oropharyngeal carcinomas harboring low-risk human papillomavirus.

Although the association between high-risk (HR) subtypes of human papillomavirus (HPV) and oropharyngeal carcinoma (OC) is well established, the role and biologic significance of low-risk (LR) HPV in these tumors remains poorly understood. In this series, we present 4 OCs with LR-HPV positivity by in situ hybridization (ISH). The cases occurred in 3 males and 1 female with a mean age of 67.8 years. All tumors demonstrated a papillary/exophytic architecture, and 2 showed overt stromal invasion. Morphologically, the tumors exhibited a spectrum ranging from keratinizing neoplasms with relatively low-grade cytologic features to predominantly non-keratinizing tumors with higher-grade cytology. Glandular differentiation was identified in one case. Koilocytic change was present in all tumors, while prominent intraepithelial neutrophils were identified in two cases. A possible squamous papilloma precursor lesion was present in two cases. All tumors were positive for LR-HPV RNA ISH and negative for HR-HPV RNA ISH. p16 immunohistochemistry was negative in 3 cases and equivocal in one. HPV6 DNA was confirmed in both tumors subjected to sequencing, which additionally identified alterations involving TERT, PIK3CA, FAT1, KRAS, and EP300. Rare OCs may demonstrate transcriptionally active LR-HPV expression and harbor molecular alterations commonly encountered in conventional HPV-independent squamous cell carcinoma. These tumors exhibit morphologic overlap with squamous papilloma, Schneiderian-like papilloma, adenosquamous carcinoma, mucoepidermoid carcinoma, and DEK::AFF2-rearranged carcinoma. While the significance of LR-HPV in these neoplasms remains uncertain, the findings expand the spectrum of HPV-associated lesions encountered in the oropharynx and provide a foundation for future mechanistic studies.